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JAK-STAT Signalling Pathway in Cancer
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JAK-STAT Signalling Pathway in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 November 2019) | Viewed by 139112

Special Issue Editors

Dr. Andrew J. Brooks

E-Mail Website
Guest Editor
Diamantina Institute, The University of Queensland, Level 5, Translational Research Institute 37 Kent Street, Woolloongabba, QLD 4102, Australia
Interests: cytokine receptors kinases; JAK2; STAT5; STAT3
Dr. Tracy Putoczki

E-Mail Website
Guest Editor
Personalized Oncology Division, The Walter and Eliza Hall Institute of Medical Research
Interests: cancer; cytokines; inflammation; microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The JAK-STAT signalling pathway is a major contributor to haematological malignancies, however this signalling pathway is also known to play key roles in promoting solid tumour growth and metastasis. In addition, JAK-STAT signalling has been shown to contribute to a pro-tumorigenic microenvironment through induction of inflammatory responses. JAK-STAT signalling is normally activated by cytokine binding to cytokine receptors as well as some G protein-coupled receptors (GPCRs). Constitutive STAT signalling in cancer can commonly occur due to activating mutations in cytokine receptors or JAKs, while activating mutations in STATs are rare. Mutations that result in increased sensitivity to cytokine activation or extended length of JAK-STAT signalling can also contribute to cancer. Understanding the mechanisms that drive JAK-STAT signalling will be fundamental to our understanding of cancer, the development of novel therapeutic approaches, and ultimately to improved patient outcomes.

Dr. Andrew J. Brooks
Dr. Tracy Putoczki
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cancer
  • Cytokine
  • Cytokine receptor
  • Inflammation
  • JAK
  • STAT
  • Suppressor Of Cytokine Signalling (SOCS)

Published Papers (22 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 158 KiB  
Editorial
JAK-STAT Signalling Pathway in Cancer
by Andrew J. Brooks and Tracy Putoczki
Cancers 2020, 12(7), 1971; https://doi.org/10.3390/cancers12071971 - 20 Jul 2020
Cited by 67 | Viewed by 5202
Abstract
n/a Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)

Research

Jump to: Editorial, Review, Other

16 pages, 2884 KiB  
Article
STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer
by Taylor T. Chrisikos, Yifan Zhou, Haiyan S. Li, Rachel L. Babcock, Xianxiu Wan, Bhakti Patel, Kathryn Newton, James J. Mancuso and Stephanie S. Watowich
Cancers 2020, 12(1), 128; https://doi.org/10.3390/cancers12010128 - 4 Jan 2020
Cited by 15 | Viewed by 4069
Abstract
Conventional dendritic cells (cDCs) are a critical immune population, composed of multiple subsets, and responsible for controlling adaptive immunity and tolerance. Although migratory type 1 cDCs (CD103+ cDC1s in mice) are necessary to mount CD8+ T cell-mediated anti-tumor immunity, whether and [...] Read more.
Conventional dendritic cells (cDCs) are a critical immune population, composed of multiple subsets, and responsible for controlling adaptive immunity and tolerance. Although migratory type 1 cDCs (CD103+ cDC1s in mice) are necessary to mount CD8+ T cell-mediated anti-tumor immunity, whether and how tumors modulate CD103+ cDC1 function remain understudied. Signal Transducer and Activator of Transcription 3 (STAT3) mediates the intracellular signaling of tumor-associated immunosuppressive cytokines, such as interleukin (IL)-10; thus, we hypothesized that STAT3 restrained anti-tumor immune responses elicited by CD103+ cDC1s. Herein, we show that in vitro-derived STAT3-deficient (Stat3∆/∆) CD103+ cDC1s are refractory to the inhibitory effects of IL-10 on Toll-like receptor 3 (TLR3) agonist-induced maturation responses. In a tumor vaccination approach, we found Stat3∆/∆ CD103+ cDC1s restrained mammary gland tumor growth and increased mouse survival more effectively than STAT3-sufficient CD103+ cDC1s. In addition, vaccination with Stat3∆/∆ CD103+ cDC1s elicited increased amounts of tumor antigen-specific CD8+ T cells and IFN-γ+ CD4+ T cells in tumors and tumor-draining lymph nodes versus phosphate-buffered saline (PBS)-treated animals. Furthermore, IL-10 receptor-deficient CD103+ cDC1s controlled tumor growth to a similar degree as Stat3∆/∆ CD103+ cDC1s. Taken together, our data reveal an inhibitory role for STAT3 in CD103+ cDC1 maturation and regulation of anti-tumor immunity. Our results also suggest IL-10 is a key factor eliciting immunosuppressive STAT3 signaling in CD103+ cDC1s in breast cancer. Thus, inhibition of STAT3 in cDC1s may provide an important strategy to improve their efficacy in tumor vaccination approaches and cDC1-mediated control of anti-tumor immunity. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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13 pages, 1706 KiB  
Article
Whole Genome Sequencing of Spontaneously Occurring Rat Natural Killer Large Granular Lymphocyte Leukemia Identifies JAK1 Somatic Activating Mutation
by T. Tiffany Wang, Jun Yang, Shubha Dighe, Matthew W. Schmachtenberg, Nathan T. Leigh, Emily Farber, Suna Onengut-Gumuscu, David J. Feith, Aakrosh Ratan, Thomas P. Loughran, Jr. and Thomas L. Olson
Cancers 2020, 12(1), 126; https://doi.org/10.3390/cancers12010126 - 3 Jan 2020
Cited by 2 | Viewed by 3330
Abstract
Large granular lymphocyte (LGL) leukemia arises spontaneously in elderly Fischer (F344) rats. This rodent model has been shown to emulate many aspects of the natural killer (NK) variant of human LGL leukemia. Previous transplantation of leukemic material into young F344 rats resulted in [...] Read more.
Large granular lymphocyte (LGL) leukemia arises spontaneously in elderly Fischer (F344) rats. This rodent model has been shown to emulate many aspects of the natural killer (NK) variant of human LGL leukemia. Previous transplantation of leukemic material into young F344 rats resulted in several strains of rat NK (RNK) primary leukemic cells. One strain, RNK-16, was adapted into the RNK-16 cell line and established as an aggressive NK-LGL leukemia model. Whole genome sequencing of the RNK-16 cell line identified 255,838 locations where the RNK16 had an alternate allele that was different from F344, including a mutation in Jak1. Functional studies showed Jak1 Y1034C to be a somatic activating mutation that mediated increased STAT signaling, as assessed by phosphoprotein levels. Sanger sequencing of Jak1 in RNK-1, -3, -7, and -16 found only RNK-16 to harbor the Y1034C Jak1 mutation. In vivo studies revealed that rats engrafted with RNK-16 primary material developed leukemia more rapidly than those engrafted with RNK-1, -3, and -7. Additionally, ex vivo RNK-16 spleen cells from leukemic rats exhibited increased STAT1, STAT3, and STAT5 phosphorylation compared to other RNK strains. Therefore, we report and characterize a novel gain-of-function Jak1 mutation in a spontaneous LGL leukemia model that results in increased downstream STAT signaling. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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20 pages, 3324 KiB  
Article
Characterization of JAK1 Pseudokinase Domain in Cytokine Signaling
by Juuli Raivola, Teemu Haikarainen and Olli Silvennoinen
Cancers 2020, 12(1), 78; https://doi.org/10.3390/cancers12010078 - 27 Dec 2019
Cited by 21 | Viewed by 5659
Abstract
The Janus kinase-signal transducer and activator of transcription protein (JAK-STAT) pathway mediates essential biological functions from immune responses to haematopoiesis. Deregulated JAK-STAT signaling causes myeloproliferative neoplasms, leukaemia, and lymphomas, as well as autoimmune diseases. Thereby JAKs have gained significant relevance as therapeutic targets. [...] Read more.
The Janus kinase-signal transducer and activator of transcription protein (JAK-STAT) pathway mediates essential biological functions from immune responses to haematopoiesis. Deregulated JAK-STAT signaling causes myeloproliferative neoplasms, leukaemia, and lymphomas, as well as autoimmune diseases. Thereby JAKs have gained significant relevance as therapeutic targets. However, there is still a clinical need for better JAK inhibitors and novel strategies targeting regions outside the conserved kinase domain have gained interest. In-depth knowledge about the molecular details of JAK activation is required. For example, whether the function and regulation between receptors is conserved remains an open question. We used JAK-deficient cell-lines and structure-based mutagenesis to study the function of JAK1 and its pseudokinase domain (JH2) in cytokine signaling pathways that employ JAK1 with different JAK heterodimerization partner. In interleukin-2 (IL-2)-induced STAT5 activation JAK1 was dominant over JAK3 but in interferon-γ (IFNγ) and interferon-α (IFNα) signaling both JAK1 and heteromeric partner JAK2 or TYK2 were both indispensable for STAT1 activation. Moreover, IL-2 signaling was strictly dependent on both JAK1 JH1 and JH2 but in IFNγ signaling JAK1 JH2 rather than kinase activity was required for STAT1 activation. To investigate the regulatory function, we focused on two allosteric regions in JAK1 JH2, the ATP-binding pocket and the αC-helix. Mutating L633 at the αC reduced basal and cytokine induced activation of STAT in both JAK1 wild-type (WT) and constitutively activated mutant backgrounds. Moreover, biochemical characterization and comparison of JH2s let us depict differences in the JH2 ATP-binding and strengthen the hypothesis that de-stabilization of the domain disturbs the regulatory JH1-JH2 interaction. Collectively, our results bring mechanistic understanding about the function of JAK1 in different receptor complexes that likely have relevance for the design of specific JAK modulators. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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17 pages, 4960 KiB  
Article
In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment
by Filippo Severin, Federica Frezzato, Andrea Visentin, Veronica Martini, Valentina Trimarco, Samuela Carraro, Elena Tibaldi, Anna Maria Brunati, Francesco Piazza, Gianpietro Semenzato, Monica Facco and Livio Trentin
Cancers 2019, 11(12), 1939; https://doi.org/10.3390/cancers11121939 - 4 Dec 2019
Cited by 35 | Viewed by 3768
Abstract
The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the [...] Read more.
The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the modulation of JAK2/STAT3 pathway in CLL by BMSCs and its targeting with AG490 (JAK2 inhibitor) or Stattic (STAT3 inhibitor). B cells collected from controls and CLL patients, were treated with medium alone, ibrutinib, JAK/Signal Transducer and Activator of Transcription (STAT) inhibitors, or both drugs, in the presence of absence of BMSCs. JAK2/STAT3 axis was evaluated by western blotting, flow cytometry, and confocal microscopy. We demonstrated that STAT3 was phosphorylated in Tyr705 in the majority of CLL patients at basal condition, and increased following co-cultures with BMSCs or IL-6. Treatment with AG490, but not Stattic, caused STAT3 and Lyn dephosphorylation, through re-activation of SHP-1, and triggered CLL apoptosis even when leukemic cells were cultured on BMSC layers. Moreover, while BMSCs hamper ibrutinib activity, the combination of ibrutinib+JAK/STAT inhibitors increase ibrutinib-mediated leukemic cell death, bypassing the pro-survival stimuli derived from BMSCs. We herein provide evidence that JAK2/STAT3 signaling might play a key role in the regulation of CLL-BMSC interactions and its inhibition enhances ibrutinib, counteracting the bone marrow niche. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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22 pages, 2911 KiB  
Article
JAK2 Inhibition Impairs Proliferation and Sensitises Cervical Cancer Cells to Cisplatin-Induced Cell Death
by Ethan L. Morgan and Andrew Macdonald
Cancers 2019, 11(12), 1934; https://doi.org/10.3390/cancers11121934 - 4 Dec 2019
Cited by 41 | Viewed by 4775
Abstract
Persistent infection with high-risk human papillomavirus (HPV) is the underlying cause of ~5% of all human cancers, including the majority of cervical carcinomas and many other ano-genital and oral cancers. A major challenge remains to identify key host targets of HPV and to [...] Read more.
Persistent infection with high-risk human papillomavirus (HPV) is the underlying cause of ~5% of all human cancers, including the majority of cervical carcinomas and many other ano-genital and oral cancers. A major challenge remains to identify key host targets of HPV and to reveal how they contribute to virus-mediated malignancy. The HPV E6 oncoprotein aberrantly activates the signal transducer and activator of transcription 3 (STAT3) transcription factor and this is achieved by a virus-driven increase in the levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in HPV positive cervical cancers cells. Crucially, STAT3 activity is essential for the proliferation and survival of cervical cancer cells, suggesting that targeting STAT3 may have therapeutic potential. Unfortunately, the development of direct STAT3 inhibitors has been problematic in the clinic due to toxicity issues identified in early stage trials. To overcome this issue, we focused on the protein Janus kinase 2 (JAK2), which phosphorylates STAT3 and is essential for STAT3 activation. Here, we demonstrate that inhibiting JAK2 reduces cell proliferation and induces apoptosis in HPV transformed cervical cancer cells. We further establish that this is due to inhibition of phosphorylation of the JAK2 substrates STAT3 and STAT5. Finally, we demonstrate that the clinically available JAK2 inhibitor Ruxolitinib synergises with cisplatin in inducing apoptosis, highlighting JAK2 as a promising therapeutic target in HPV-driven cancers. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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16 pages, 2197 KiB  
Article
Enzymatic Characterization of Wild-Type and Mutant Janus Kinase 1
by Nicholas P. D. Liau, Artem Laktyushin, Rhiannon Morris, Jarrod J. Sandow, Nicos A. Nicola, Nadia J. Kershaw and Jeffrey J. Babon
Cancers 2019, 11(11), 1701; https://doi.org/10.3390/cancers11111701 - 1 Nov 2019
Cited by 9 | Viewed by 4065
Abstract
Janus kinases (JAKs) are found constitutively associated with cytokine receptors and are present in an inactive state prior to cytokine exposure. Activating mutations of JAKs are causative for a number of leukemias, lymphomas, and myeloproliferative diseases. In particular, the JAK2V617F mutant is [...] Read more.
Janus kinases (JAKs) are found constitutively associated with cytokine receptors and are present in an inactive state prior to cytokine exposure. Activating mutations of JAKs are causative for a number of leukemias, lymphomas, and myeloproliferative diseases. In particular, the JAK2V617F mutant is found in most human cases of polycythemia vera, a disease characterized by over-production of erythrocytes. The V617F mutation is found in the pseudokinase domain of JAK2 and it leads to cytokine-independent activation of the kinase, as does the orthologous mutation in other JAK-family members. The mechanism whereby this mutation hyperactivates these kinases is not well understood, primarily due to the fact that the full-length JAK proteins are difficult to produce for structural and kinetic studies. Here we have overcome this limitation to perform a series of enzymatic analyses on full-length JAK1 and its constitutively active mutant form (JAK1V658F). Consistent with previous studies, we show that the presence of the pseudokinase domain leads to a dramatic decrease in enzymatic activity with no further decrease from the presence of the FERM or SH2 domains. However, we find that the mutant kinase, in vitro, is indistinguishable from the wild-type enzyme in every measurable parameter tested: KM (ATP), KM (substrate), kcat, receptor binding, thermal stability, activation rate, dephosphorylation rate, and inhibitor affinity. These results show that the V658F mutation does not enhance the intrinsic enzymatic activity of JAK. Rather this data is more consistent with a model in which there are cellular processes and interactions that prevent JAK from being activated in the absence of cytokine and it is these constraints that are affected by disease-causing mutations. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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20 pages, 7577 KiB  
Article
The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation
by Ji-Hyang Kim, Hack Sun Choi, Su-Lim Kim and Dong-Sun Lee
Cancers 2019, 11(10), 1527; https://doi.org/10.3390/cancers11101527 - 10 Oct 2019
Cited by 33 | Viewed by 9291
Abstract
Cancer stem cells (CSCs) have unique properties, including self-renewal, differentiation, and chemoresistance. In this study, we found that p21-activated kinase (PAK1) inhibitor (Group I, PAK inhibitor, IPA-3) and inactivator (ivermectin) treatments inhibit cell proliferation and that tumor growth of PAK1-knockout cells in a [...] Read more.
Cancer stem cells (CSCs) have unique properties, including self-renewal, differentiation, and chemoresistance. In this study, we found that p21-activated kinase (PAK1) inhibitor (Group I, PAK inhibitor, IPA-3) and inactivator (ivermectin) treatments inhibit cell proliferation and that tumor growth of PAK1-knockout cells in a mouse model is significantly reduced. IPA-3 and ivermectin inhibit CSC formation. PAK1 physically interacts with Janus Kinase 2 (JAK2), and JAK2 inhibitor (TG101209) treatment inhibits mammosphere formation and reduces the nuclear PAK1 protein level. PAK1 interacts with signal transducer and activator of transcription 3 (Stat3), and PAK1 and Stat3 colocalize in the nucleus. We show through electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and reporter assays that the PAK1/Stat3 complex binds to the IL-6 promoter and regulates the transcription of the IL-6 gene. Inhibition of PAK1 and JAK2 in mammospheres reduces the nuclear pStat3 and extracellular IL-6 levels. PAK1 inactivation inhibits CSC formation by decreasing pStat3 and extracellular IL-6 levels. Our results reveal that JAK2/PAK1 dysregulation inhibits the Stat3 signaling pathway and CSC formation, the PAK1/Stat3 complex regulates IL-6 gene expression, PAK1/Stat3 signaling regulates CSC formation, and PAK1 may be an important target for treating breast cancer. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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21 pages, 3345 KiB  
Article
Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma
by Reetobrata Basu, Prateek Kulkarni, Yanrong Qian, Christopher Walsh, Pranay Arora, Emily Davis, Silvana Duran-Ortiz, Kevin Funk, Diego Ibarra, Colin Kruse, Samuel Mathes, Todd McHugh, Alison Brittain, Darlene E. Berryman, Edward O. List, Shigeru Okada and John J. Kopchick
Cancers 2019, 11(9), 1352; https://doi.org/10.3390/cancers11091352 - 12 Sep 2019
Cited by 21 | Viewed by 6344
Abstract
Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette [...] Read more.
Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette containing multidrug efflux pumps (ABC-transporters). In extremely drug-resistant melanoma, ABC-transporters have also been reported to mediate drug sequestration in intracellular melanosomes, thereby reducing drug efficacy. Melanocyte-inducing transcription factor (MITF) is the master regulator of melanocyte and melanoma cell fate as well as the melanosomal machinery. MITF targets such as the oncogene MET, as well as MITF-mediated processes such as resistance to radiation therapy, are both known to be upregulated by GH. Therefore, we chose to query the direct effects of GH on MITF expression and activity towards conferring chemoresistance in melanoma. Here, we demonstrate that GH significantly upregulates MITF as well as the MITF target genes following treatment with multiple anticancer drug treatments such as chemotherapy, BRAF-inhibitors, as well as tyrosine-kinase inhibitors. GH action also upregulated MITF-regulated processes such as melanogenesis and tyrosinase activity. Significant elevation in MITF and MITF target gene expression was also observed in mouse B16F10 melanoma cells and xenografts in bovine GH transgenic (bGH) mice compared to wild-type littermates. Through pathway inhibitor analysis we identified that both the JAK2-STAT5 and SRC activities were critical for the observed effects. Additionally, a retrospective analysis of gene expression data from GTEx, NCI60, CCLE, and TCGA databases corroborated our observed correlation of MITF function and GH action. Therefore, we present in vitro, in vivo, and in silico evidence which strongly implicates the GH–GHR axis in inducing chemoresistance in human melanoma by driving MITF-regulated and ABC-transporter-mediated drug clearance pathways. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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12 pages, 1790 KiB  
Article
A Mouse Model to Assess STAT3 and STAT5A/B Combined Inhibition in Health and Disease Conditions
by Herwig P. Moll, Julian Mohrherr, Leander Blaas, Monica Musteanu, Patricia Stiedl, Beatrice Grabner, Katalin Zboray, Margit König, Dagmar Stoiber, Thomas Rülicke, Sabine Strehl, Robert Eferl and Emilio Casanova
Cancers 2019, 11(9), 1226; https://doi.org/10.3390/cancers11091226 - 22 Aug 2019
Cited by 3 | Viewed by 3409
Abstract
Genetically-engineered mouse models (GEMMs) lacking diseased-associated gene(s) globally or in a tissue-specific manner represent an attractive tool with which to assess the efficacy and toxicity of targeted pharmacological inhibitors. Stat3 and Stat5a/b transcription factors have been implicated in several pathophysiological conditions, and pharmacological [...] Read more.
Genetically-engineered mouse models (GEMMs) lacking diseased-associated gene(s) globally or in a tissue-specific manner represent an attractive tool with which to assess the efficacy and toxicity of targeted pharmacological inhibitors. Stat3 and Stat5a/b transcription factors have been implicated in several pathophysiological conditions, and pharmacological inhibition of both transcription factors has been proposed to treat certain diseases, such as malignancies. To model combined inhibition of Stat3 and Stat5a/b we have developed a GEMM harboring a flox Stat3-Stat5a/b allele (Stat5/3loxP/loxP mice) and generated mice lacking Stat3 and Stat5a/b in hepatocytes (Stat5/3Δhep/Δhep). Stat5/3Δhep/Δhep mice exhibited a marked reduction of STAT3, STAT5A and STAT5B proteins in the liver and developed steatosis, a phenotype that resembles mice lacking Stat5a/b in hepatocytes. In addition, embryonic deletion of Stat3 and Stat5a/b (Stat5/3Δ/Δ mice) resulted in lethality, similar to Stat3Δ/Δ mice. This data illustrates that Stat5/3loxP/loxP mice are functional and can be used as a valuable tool to model the combined inhibition of Stat3 and Stat5a/b in tumorigenesis and other diseases. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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25 pages, 4777 KiB  
Article
Hyper-Activation of STAT3 Sustains Progression of Non-Papillary Basal-Type Bladder Cancer via FOSL1 Regulome
by Luisa Benerini Gatta, Laura Melocchi, Mattia Bugatti, Francesco Missale, Silvia Lonardi, Benedetta Zanetti, Luca Cristinelli, Sandra Belotti, Claudio Simeone, Roberto Ronca, Elisabetta Grillo, Sara Licini, Debora Bresciani, Regina Tardanico, Szeman Ruby Chan, Emanuele Giurisato, Stefano Calza and William Vermi
Cancers 2019, 11(9), 1219; https://doi.org/10.3390/cancers11091219 - 21 Aug 2019
Cited by 31 | Viewed by 3868
Abstract
Urothelial bladder cancer (UBC) are classified into luminal and basal subtypes showing distinct molecular features and clinical behaviour. Recent in silico data have proposed the activation on the Signal Transducer and Activator of Transcription 3 (STAT3) as relevant transcription factor in UBC. To [...] Read more.
Urothelial bladder cancer (UBC) are classified into luminal and basal subtypes showing distinct molecular features and clinical behaviour. Recent in silico data have proposed the activation on the Signal Transducer and Activator of Transcription 3 (STAT3) as relevant transcription factor in UBC. To answer this question, we have combined the retrospective analysis of clinical samples, functional assays on cell lines, interrogation of public UBC datasets and a murine model of basal-type UBC. Immunohistochemistry on a retrospective UBC cohort uncovered that STAT3 Y705 phosphorylation (pSTAT3) is significantly increased in infiltrating basal-type UBC compared to luminal UBC. In vitro, STAT3 silencing in UBC cell lines significantly reduced tumor cell viability and invasion. Gene expression profile of UBC cell lines combined with the analysis of the Cancer Genome Atlas (TCGA) and GSE32894 UBC datasets showed that increased expression of a set of STAT3 targets predicts basal-type, propensity to local progression and worse prognosis. MYC and FOSL1 represent relevant STAT3 downstream targets, as validated by their co-localization in pSTAT3+ UBC cancer cells. These findings were largely reproduced in the BBN-induced murine model of basal-type UBC. Of note, FOSL1 protein resulted strongly expressed in the non-papillary UBC pathway and FOSL1-regulated transcripts were significantly enriched in the transition from NMIBC to MIBC, as indicated by the interrogation of the GSE32894 dataset. The blockade of the STAT3 pathway might represent a novel treatment option for these neoplasms. Monitoring pSTAT3 and the downstream targets, particularly FOSL1, could provide meaningful levels of UBC stratification. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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13 pages, 3000 KiB  
Article
A Novel Type of Blood Biomarker: Distinct Changes of Cytokine-Induced STAT Phosphorylation in Blood T Cells Between Colorectal Cancer Patients and Healthy Individuals
by Jae Won Yun, Sejoon Lee, Hye Mi Kim, Sejong Chun, Edgar G. Engleman, Hee Cheol Kim and Eun-Suk Kang
Cancers 2019, 11(8), 1157; https://doi.org/10.3390/cancers11081157 - 12 Aug 2019
Cited by 13 | Viewed by 4861
Abstract
Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Although early diagnosis and treatment is the most successful strategy for improving patient survival, feasible and sensitive blood biomarkers for CRC screening remain elusive. Methods: Sixty-five CRC [...] Read more.
Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Although early diagnosis and treatment is the most successful strategy for improving patient survival, feasible and sensitive blood biomarkers for CRC screening remain elusive. Methods: Sixty-five CRC patients and thirty-three healthy individuals were enrolled. Peripheral blood (PB) and tumor tissues from CRC patients, and PB from healthy individuals were subjected to immunophenotyping and phospho-flow analysis of cytokine-induced phosphorylated STAT (CIPS). Logistic regression was used as a classifier that separates CRC patients from healthy individuals. Results: The proportion of regulatory T cells was increased in PB from CRC patients compared to PB from healthy individuals (p < 0.05). Interestingly, peripheral T cells share several cytokine-induced phosphorylated STAT (CIPS) signatures with T cells from CRC tumor-sites. Additionally, a classifier was made using two signatures distinct between T cells from CRC patients and T cells from healthy individuals. The AUCs (area under curves) of the classifier were 0.88 in initial cohort and 0.94 in the additional validation cohort. Overall AUC was 0.94 with sensitivity of 91% and specificity of 88%. Conclusion: This study highlights that immune cell signatures in peripheral blood could offer a new type of biomarker for CRC screening. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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Review

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24 pages, 829 KiB  
Review
TYK2 in Tumor Immunosurveillance
by Anzhelika Karjalainen, Stephen Shoebridge, Milica Krunic, Natalija Simonović, Graham Tebb, Sabine Macho-Maschler, Birgit Strobl and Mathias Müller
Cancers 2020, 12(1), 150; https://doi.org/10.3390/cancers12010150 - 8 Jan 2020
Cited by 18 | Viewed by 6034
Abstract
We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 [...] Read more.
We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue ‘Targeting STAT3 and STAT5 in Cancer’ of Cancers. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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23 pages, 1603 KiB  
Review
Energy Metabolism in Cancer: The Roles of STAT3 and STAT5 in the Regulation of Metabolism-Related Genes
by Arturo Valle-Mendiola and Isabel Soto-Cruz
Cancers 2020, 12(1), 124; https://doi.org/10.3390/cancers12010124 - 3 Jan 2020
Cited by 48 | Viewed by 7467
Abstract
A central characteristic of many types of cancer is altered energy metabolism processes such as enhanced glucose uptake and glycolysis and decreased oxidative metabolism. The regulation of energy metabolism is an elaborate process involving regulatory proteins such as HIF (pro-metastatic protein), which reduces [...] Read more.
A central characteristic of many types of cancer is altered energy metabolism processes such as enhanced glucose uptake and glycolysis and decreased oxidative metabolism. The regulation of energy metabolism is an elaborate process involving regulatory proteins such as HIF (pro-metastatic protein), which reduces oxidative metabolism, and some other proteins such as tumour suppressors that promote oxidative phosphorylation. In recent years, it has been demonstrated that signal transducer and activator of transcription (STAT) proteins play a pivotal role in metabolism regulation. STAT3 and STAT5 are essential regulators of cytokine- or growth factor-induced cell survival and proliferation, as well as the crosstalk between STAT signalling and oxidative metabolism. Several reports suggest that the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of hypoxia-inducible factors and therefore, the alteration of mitochondrial activity. It seems that STAT proteins function as an integrative centre for different growth and survival signals for energy and respiratory metabolism. This review summarises the functions of STAT3 and STAT5 in the regulation of some metabolism-related genes and the importance of oxygen in the tumour microenvironment to regulate cell metabolism, particularly in the metabolic pathways that are involved in energy production in cancer cells. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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18 pages, 1685 KiB  
Review
STAT3 Activation and Oncogenesis in Lymphoma
by Fen Zhu, Kevin Boyang Wang and Lixin Rui
Cancers 2020, 12(1), 19; https://doi.org/10.3390/cancers12010019 - 19 Dec 2019
Cited by 49 | Viewed by 5674
Abstract
Signal transducer and activator of transcription 3 (STAT3) is an important and the most studied transcription factor in the Janus kinase (JAK)/STAT signaling pathway. STAT3 mediates the expression of various genes that play a critical role in many cellular and biological processes, such [...] Read more.
Signal transducer and activator of transcription 3 (STAT3) is an important and the most studied transcription factor in the Janus kinase (JAK)/STAT signaling pathway. STAT3 mediates the expression of various genes that play a critical role in many cellular and biological processes, such as cell proliferation, survival, differentiation, migration, angiogenesis, and inflammation. STAT3 and associated JAKs are activated and tightly regulated by a variety of cytokines and growth factors and their receptors in normal immune responses. However, abnormal expression of STAT3 leads to its constitutive activation, which promotes malignant transformation and tumor progression through oncogenic gene expression in numerous human cancers. Human lymphoma is a heterogeneous malignancy of T and B lymphocytes. Constitutive signaling by STAT3 is an oncogenic driver in several types of B-cell lymphoma and most of T-cell lymphomas. Aberrant STAT3 activation can also induce inappropriate expression of genes involved in tumor immune evasion such as PD-L1. In this review, we focus on the oncogenic role of STAT3 in human lymphoma and highlight potential therapeutic intervention by targeting JAK/STAT3 signaling. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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26 pages, 1413 KiB  
Review
JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression
by Katie L. Owen, Natasha K. Brockwell and Belinda S. Parker
Cancers 2019, 11(12), 2002; https://doi.org/10.3390/cancers11122002 - 12 Dec 2019
Cited by 349 | Viewed by 25090
Abstract
Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and [...] Read more.
Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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18 pages, 2725 KiB  
Review
Deleterious and Oncogenic Mutations in the IL7RA
by Lívia Weijenborg Campos, Leonardo Granato Pissinato and José Andrés Yunes
Cancers 2019, 11(12), 1952; https://doi.org/10.3390/cancers11121952 - 5 Dec 2019
Cited by 13 | Viewed by 5266
Abstract
Interleukin 7 (IL-7) is a critical cytokine that plays a fundamental role in B- and T-cell development and in acute lymphoblastic leukemia (ALL). Its receptor (IL7R) is a transmembrane heterodimer formed by the IL7Rα and the IL2Rγ chain (γc). The IL7R signals through [...] Read more.
Interleukin 7 (IL-7) is a critical cytokine that plays a fundamental role in B- and T-cell development and in acute lymphoblastic leukemia (ALL). Its receptor (IL7R) is a transmembrane heterodimer formed by the IL7Rα and the IL2Rγ chain (γc). The IL7R signals through the JAK/STAT pathway. Loss-of-function mutations and some polymorphisms of the IL7Rα were associated to immunodeficiency and inflammatory diseases, respectively. Gain-of-function mutations were described in T-cell ALL and in high risk precursor B-cell ALL. Most confirmed loss-of-function mutations occur in the extracellular part of the IL7Rα while oncogenic mutations are exclusively found in the extracellular juxtamembrane (EJM) or transmembrane regions. Oncogenic mutations promote either IL7Rα/IL7Rα homodimerization and constitutive signaling, or increased affinity to γc or IL-7. This work presents a review on IL7Rα polymorphisms/mutations and attempts to present a classification based on their structural consequences and resulting biological activity. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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23 pages, 1196 KiB  
Review
STAT5A and STAT5B—Twins with Different Personalities in Hematopoiesis and Leukemia
by Barbara Maurer, Sebastian Kollmann, Judith Pickem, Andrea Hoelbl-Kovacic and Veronika Sexl
Cancers 2019, 11(11), 1726; https://doi.org/10.3390/cancers11111726 - 4 Nov 2019
Cited by 35 | Viewed by 6392
Abstract
The transcription factors STAT5A and STAT5B have essential roles in survival and proliferation of hematopoietic cells—which have been considered largely redundant. Mutations of upstream kinases, copy number gains, or activating mutations in STAT5A, or more frequently in STAT5B, cause altered hematopoiesis and cancer. [...] Read more.
The transcription factors STAT5A and STAT5B have essential roles in survival and proliferation of hematopoietic cells—which have been considered largely redundant. Mutations of upstream kinases, copy number gains, or activating mutations in STAT5A, or more frequently in STAT5B, cause altered hematopoiesis and cancer. Interfering with their activity by pharmacological intervention is an up-and-coming therapeutic avenue. Precision medicine requests detailed knowledge of STAT5A’s and STAT5B’s individual functions. Recent evidence highlights the privileged role for STAT5B over STAT5A in normal and malignant hematopoiesis. Here, we provide an overview on their individual functions within the hematopoietic system. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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17 pages, 741 KiB  
Review
STAT3 Dysregulation in Mature T and NK Cell Lymphomas
by Angelina Seffens, Alberto Herrera, Cosmin Tegla, Terkild B. Buus, Kenneth B. Hymes, Niels Ødum, Larisa J. Geskin and Sergei B. Koralov
Cancers 2019, 11(11), 1711; https://doi.org/10.3390/cancers11111711 - 2 Nov 2019
Cited by 25 | Viewed by 5945
Abstract
T cell lymphomas comprise a distinct class of non-Hodgkin’s lymphomas, which include mature T and natural killer (NK) cell neoplasms. While each malignancy within this group is characterized by unique clinicopathologic features, dysregulation in the Janus tyrosine family of kinases/Signal transducer and activator [...] Read more.
T cell lymphomas comprise a distinct class of non-Hodgkin’s lymphomas, which include mature T and natural killer (NK) cell neoplasms. While each malignancy within this group is characterized by unique clinicopathologic features, dysregulation in the Janus tyrosine family of kinases/Signal transducer and activator of transcription (JAK/STAT) signaling pathway, specifically aberrant STAT3 activation, is a common feature among these lymphomas. The mechanisms driving dysregulation vary among T cell lymphoma subtypes and include activating mutations in upstream kinases or STAT3 itself, formation of oncogenic kinases which drive STAT3 activation, loss of negative regulators of STAT3, and the induction of a pro-tumorigenic inflammatory microenvironment. Constitutive STAT3 activation has been associated with the expression of targets able to increase pro-survival signals and provide malignant fitness. Patients with dysregulated STAT3 signaling tend to have inferior clinical outcomes, which underscores the importance of STAT3 signaling in malignant progression. Targeting of STAT3 has shown promising results in pre-clinical studies in T cell lymphoma lines, ex-vivo primary malignant patient cells, and in mouse models of disease. However, targeting this pleotropic pathway in patients has proven difficult. Here we review the recent contributions to our understanding of the role of STAT3 in T cell lymphomagenesis, mechanisms driving STAT3 activation in T cell lymphomas, and current efforts at targeting STAT3 signaling in T cell malignancies. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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17 pages, 839 KiB  
Review
Jak-Stat Signaling Induced by Interleukin-6 Family Cytokines in Hepatocellular Carcinoma
by Juliane Lokau, Victor Schoeder, Johannes Haybaeck and Christoph Garbers
Cancers 2019, 11(11), 1704; https://doi.org/10.3390/cancers11111704 - 1 Nov 2019
Cited by 82 | Viewed by 5547
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. It can be caused by chronic liver cell injury with resulting sustained inflammation, e.g., triggered by infections with hepatitis viruses B (HBV) and C (HCV). Death of hepatocytes leads to the [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. It can be caused by chronic liver cell injury with resulting sustained inflammation, e.g., triggered by infections with hepatitis viruses B (HBV) and C (HCV). Death of hepatocytes leads to the activation of compensatory mechanisms, which can ultimately result in liver fibrosis and cirrhosis. Another common feature is the infiltration of the liver with inflammatory cells, which secrete cytokines and chemokines that act directly on the hepatocytes. Among several secreted proteins, members of the interleukin-6 (IL-6) family of cytokines have emerged as important regulatory proteins that might constitute an attractive target for therapeutic intervention. The IL-6-type cytokines activate multiple intracellular signaling pathways, and especially the Jak/STAT cascade has been shown to be crucial for HCC development. In this review, we give an overview about HCC pathogenesis with respect to IL-6-type cytokines and the Jak/STAT pathway. We highlight the role of mutations in genes encoding several proteins involved in the cytokine/Jak/STAT axis and summarize current knowledge about IL-6 family cytokines in this context. We further discuss possible anti-cytokine therapies for HCC patients in comparison to already established therapies. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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28 pages, 4850 KiB  
Review
ADAM17: An Emerging Therapeutic Target for Lung Cancer
by Mohamed I. Saad, Stefan Rose-John and Brendan J. Jenkins
Cancers 2019, 11(9), 1218; https://doi.org/10.3390/cancers11091218 - 21 Aug 2019
Cited by 55 | Viewed by 8040
Abstract
Lung cancer is the leading cause of cancer-related mortality, which histologically is classified into small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer diagnoses, with the majority of patients presenting with lung adenocarcinoma [...] Read more.
Lung cancer is the leading cause of cancer-related mortality, which histologically is classified into small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer diagnoses, with the majority of patients presenting with lung adenocarcinoma (LAC). KRAS mutations are a major driver of LAC, and are closely related to cigarette smoking, unlike mutations in the epidermal growth factor receptor (EGFR) which arise in never-smokers. Although the past two decades have seen fundamental progress in the treatment and diagnosis of NSCLC, NSCLC still is predominantly diagnosed at an advanced stage when therapeutic interventions are mostly palliative. A disintegrin and metalloproteinase 17 (ADAM17), also known as tumour necrosis factor-α (TNFα)-converting enzyme (TACE), is responsible for the protease-driven shedding of more than 70 membrane-tethered cytokines, growth factors and cell surface receptors. Among these, the soluble interleukin-6 receptor (sIL-6R), which drives pro-inflammatory and pro-tumourigenic IL-6 trans-signaling, along with several EGFR family ligands, are the best characterised. This large repertoire of substrates processed by ADAM17 places it as a pivotal orchestrator of a myriad of physiological and pathological processes associated with the initiation and/or progression of cancer, such as cell proliferation, survival, regeneration, differentiation and inflammation. In this review, we discuss recent research implicating ADAM17 as a key player in the development of LAC, and highlight the potential of ADAM17 inhibition as a promising therapeutic strategy to tackle this deadly malignancy. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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13 pages, 3076 KiB  
Brief Report
A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma
by Christine L. White, W. Samantha N. Jayasekara, Daniel Picard, Jasmine Chen, D. Neil Watkins, Jason E. Cain, Marc Remke and Daniel J. Gough
Cancers 2019, 11(11), 1702; https://doi.org/10.3390/cancers11111702 - 1 Nov 2019
Cited by 11 | Viewed by 2874
Abstract
Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden [...] Read more.
Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden and have led to ongoing efforts to find effective targeted treatments. There is a well-recognized male bias in medulloblastoma diagnosis, although the mechanism remains unknown. Herein, we identify a sex-specific role for the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) in the Sonic Hedgehog (SHH) medulloblastoma subgroup. Specific deletion of Stat3 from granule cell precursors in a spontaneous mouse model of SHH medulloblastoma completely protects male, but not female mice from tumor initiation. Segregation of SHH medulloblastoma patients into high and low STAT3 expressing cohorts shows that low STAT3 expression correlates with improved overall survival in male patients. We observe sex specific changes in IL-10 and IL-6 expression and show that IL-6 stimulation enhances SHH-mediated gene transcription in a STAT3-dependent manner. Together these data identify STAT3 as a key molecule underpinning the sexual dimorphism in medulloblastoma. Full article
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
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